The synthesis of simple spherical or more sophisticated core-shell polymer nanoparticles is well known in polymer chemistry. Example for the former are latex beads that could be made monodisperse and of various size. Core-shell polymer particle synthesis and structures are deserted by K. Ishizu [46]. A number of parameters have to be met by the polymers to be used in animal and men. Among the most important parameters are that the polymers have to be biocompatible and the final core-shell particle must be colloidal stable in physiological environments such as blood or tissue. Furthermore, half-fife-time of the particle inside the body needs to be long enough to meet diagnostic and/or therapeutic purposes, but as short as possible to keep toxicological burden low.
Image enhancing agents, having a polymeric core including an image-enhancing compound, such as gadolinium that is bound thereto and a polymeric shell surrounding this core-imaging centre have been described by Reynolds et al. [47]. Leverge and Rolland use emulsion polymerisation to prepare simple spherical monodispersed nanoparticles for imaging purposes where the image-enhancing compound is bound to the surface of the particle [48]. In both cases, the descript particles need additional bioreactive or immunoreactive molecules to be cell specific and could not be designed for multimodal imaging due to limited structure-function capabilities.
Scientific literature describes and many patents disclose latex polymers for biomedical applications, and core-shell polymers with advanced functional properties. Most concepts for imaging and targeted therapy using nanoparticles utilises biologically active materials such as monoclonal antibodies manufacturing the appropriate specificity to reach such goals. However, the prior art fails to teach the synthesis of polymer particles for multimodal imaging with specificity for cells or cellular components without the use of additional biologically active materials. To avoid biologically active material such as foreign antibodies is demanding but also of utmost importance in this regard, since the use of biologically active material in patients is risky. In addition, enabling contrast enhanced imaging for different imaging systems (multimodal imaging) would allow to benefit from special advantages of the various systems with only one compound: spatial resolution using magnetic resonance imaging (MRI), sensitivity and specificity using positron emission tomography (PET), temporal resolution using x-ray and computed tomography (CT).
Here, we demonstrate the feasibility of multimodal in vivo imaging and detection using polymer nanoparticles. Cationic tracers such as 111In, 68Ga, polyiodinated molecules and Gd were directly bound without the necessity of a chelating conjugates into the hairy shell, the intermediate layer, of polymer nanoparticles. 68Ga-PET was used as a rapid and non-invasive imaging method to scan the whole animal and revealed the tracer mainly in the heart and the liver and to a less extend in the spleen. 111In-gamma-scintigraphy of blood and extracted organs demonstrated that this effect was due to localization in the blood compartment. T1-weighted MRI utilising the Gd-label was also achieved and displayed the circulation system. Finally, incorporation of fluorophores such as Rhodamine B into the core of the particles and the use of flow cytometry and confocal microscopy demonstrated rapid association of polymer nanoparticles with thrombocytes and particular leucocytes and monocytes. Thus, the new three compartment polymer nanoparticles enable more advanced diagnostic approaches and targeted therapy on cellular level without the use of additional biologically active materials.